MicroRNA Let-7i Negatively Regulates Cardiac Inflammation and Fibrosis
MicroRNA Let-7i Negatively Regulates Cardiac Inflammation and Fibrosis
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MicroRNA Let-7i 负向调节心脏炎症和纤维化
DOI：
10.1161/hypertensionaha.115.05548
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发表时间：
2015-10-01
期刊：
影响因子：
8.3
通讯作者：
Li, Hui-Hua
中科院分区：
文献类型：
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作者：
Wang, Xia;Wang, Hong-Xia;Li, Hui-Hua
血管紧张素II刺激成纤维细胞增殖，并显著改变导致心脏重构的基因表达模式，但这种差异的机制尚不清楚。MicroRNAs是一种新的基因表达调控机制。在此，我们利用基因芯片技术检测了小鼠心脏中miRNA和mRNA的表达模式，并探讨了它们在血管紧张素II诱导的心脏重塑中的作用。我们发现，在血管紧张素II注入的心脏中，let-7i在第3天和第7天动态下调，并且具有主要与心脏炎症和纤维化相关的最多靶点。LET-7I在培养的心脏成纤维细胞中过表达或被抑制，表明LET-7I对其靶标白介素6和胶原蛋白的表达具有抑制作用。此外，给小鼠注射let-7i显著抑制血管紧张素II诱导的心脏炎症和纤维化，并呈剂量依赖关系。相反，Let7i基因的敲除加剧了这种影响。综上所述，我们的结果清楚地表明，let-7i通过抑制心脏中IL-6和多种胶原的表达而成为血管紧张素II诱导的心脏炎症和纤维化的新的负性调节因子，并可能成为治疗高血压心肌纤维化的新的潜在治疗靶点。
Angiotensin II stimulates fibroblast proliferation and substantially alters gene expression patterns leading to cardiac remodeling, but the mechanisms for such differences are unknown. MicroRNAs are a novel mechanism for gene expression regulation. Herein, we tested the miRNA and mRNA expression patterns in mouse heart using microarray assay and investigated their role in angiotensin II–induced cardiac remodeling. We found that let-7i was dynamically downregulated in angiotensin II–infused heart at day 3 and 7 and had the most targets that were mainly associated with cardiac inflammation and fibrosis. Overexpression or knockdown of let-7i in cultured cardiac fibroblasts demonstrated that let-7i played an inhibitory effect on the expression of its targets interleukin-6 and collagens. Furthermore, delivery of let-7i to mouse significantly inhibited angiotensin II–induced cardiac inflammation and fibrosis in a dose-dependent manner. Conversely, knockdown of let-7i aggravated this effect. Together, our results clearly demonstrate that let-7i acts as a novel negative regulator of angiotensin II–induced cardiac inflammation and fibrosis by suppressing the expression of interleukin-6 and multiple collagens in the heart and may represent a new potential therapeutic target for treating hypertensive cardiac fibrosis.